Propagation of pathologic α-synuclein from kidney to brain may contribute to Parkinson’s disease

IF 21.2 1区医学 Q1 NEUROSCIENCES Nature neuroscience Pub Date : 2025-01-23 DOI:10.1038/s41593-024-01866-2

Xin Yuan, Shuke Nie, Yingxu Yang, Congcong Liu, Danhao Xia, Lanxia Meng, Yue Xia, Hua Su, Chun Zhang, Lihong Bu, Min Deng, Keqiang Ye, Jing Xiong, Liam Chen, Zhentao Zhang

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Abstract

The pathogenesis of Lewy body diseases (LBDs), including Parkinson’s disease (PD), involves α-synuclein (α-Syn) aggregation that originates in peripheral organs and spreads to the brain. PD incidence is increased in individuals with chronic renal failure, but the underlying mechanisms remain unknown. Here we observed α-Syn deposits in the kidneys of patients with LBDs and in the kidney and central nervous system of individuals with end-stage renal disease without documented LBDs. In male mice, we found that the kidney removes α-Syn from the blood, which is reduced in renal failure, causing α-Syn deposition in the kidney and subsequent spread into the brain. Intrarenal injection of α-Syn fibrils induces the propagation of α-Syn pathology from the kidney to the brain, which is blocked by renal denervation. Deletion of α-Syn in blood cells alleviates pathology in α-Syn A53T transgenic mice. Thus, the kidney may act as an initiation site for pathogenic α-Syn spread, and compromised renal function may contribute to the onset of LBDs.

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病理性α-突触核蛋白从肾向脑的增殖可能与帕金森病有关

包括帕金森病（PD）在内的路易体病（lbd）的发病机制涉及α-突触核蛋白（α-Syn）聚集，这种聚集起源于外周器官并扩散到大脑。慢性肾衰竭患者PD发病率增高，但其发病机制尚不清楚。在这里，我们观察到α-Syn沉积在lbd患者的肾脏以及无lbd的终末期肾脏疾病患者的肾脏和中枢神经系统。在雄性小鼠中，我们发现肾脏从血液中去除α-Syn，在肾功能衰竭时α-Syn减少，导致α-Syn在肾脏中沉积并随后扩散到大脑。肾内注射α-Syn原纤维可诱导α-Syn病理从肾向脑的传播，并被肾去神经支配阻断。在α-Syn A53T转基因小鼠中，血细胞中α-Syn的缺失可减轻其病理变化。因此，肾脏可能是致病性α-Syn扩散的起始位点，肾功能受损可能导致lbd的发病。

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来源期刊

Nature neuroscience 医学-神经科学

CiteScore

38.60

自引率

1.20%

发文量

212

审稿时长

1 months

期刊介绍： Nature Neuroscience, a multidisciplinary journal, publishes papers of the utmost quality and significance across all realms of neuroscience. The editors welcome contributions spanning molecular, cellular, systems, and cognitive neuroscience, along with psychophysics, computational modeling, and nervous system disorders. While no area is off-limits, studies offering fundamental insights into nervous system function receive priority. The journal offers high visibility to both readers and authors, fostering interdisciplinary communication and accessibility to a broad audience. It maintains high standards of copy editing and production, rigorous peer review, rapid publication, and operates independently from academic societies and other vested interests. In addition to primary research, Nature Neuroscience features news and views, reviews, editorials, commentaries, perspectives, book reviews, and correspondence, aiming to serve as the voice of the global neuroscience community.

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